The objective of this research proposal is to define the relationship between defects at the level of adipose tissue and regulation of hepatic glucose production (HGP) in the pathophysiology of NIDDM. In order to accomplish these goals, studies will be carried out in normal individuals and in patients with NIDDM of varying degrees of severity. These subjects will be matched in terms of age, gender, degree of general obesity, regional fat distribution, and level of habitual physical activity. Plasma free fatty acid (FFA) concentration will be either decreased (nicotinic acid infusion) or increased (intralipid plus heparin infusion) and the resultant changes in plasma glucose concentration, hepatic glucose production, and glucose disposal will be quantified. These experiments will be performed in the presence of somatostatin, both in the absence and the presence of basal concentrations of glucagon, growth hormone, and insulin. The results of these experiments should provide considerable new information as to the pathophysiology of NIDDM, a disease which is responsible for considerable morbidity and mortality not just in the United States, but in the remainder of the world as well.